The long-term goal of our program is to develop a safe and effective technique to combat various tissue ischemic damages. The specific aim of this proposal is to use our newly developed proprietary intracellular energy delivery technique to promote healing of diabetic wounds. Of the 17 million Americans with diabetes, approximately 2.5 to 4.5 million will develop a chronic wound in their lifetime. The overall cost of diabetic foot problems, including loss of productivity, could be as high as $20 billion per year. Despite thousands of dressing products developed to treat wounds, none have shown consistent effect. We propose a new approach for chronic wounds. Our central hypoth- esis is that wound tissue hypoxia results in depletion of adenosine triphosphate (ATP), which is the fundamental cause of non-healing chronic wounds, and a direct intracellular ATP delivery will improve microenvironment of wound tissue and facilitate healing process. Direct energy supply for wound treatment has never been attempted before, and the relationship between increased energy supply and wound healing process is entirely unknown. During the tenure of the Pi's NIH grant entitled "Enhanced glycolysis for hypothermic heart preservation", a new technique for direct intracellular delivery of ATP has been developed in which a special carrier is used to encapsulate ATP. The composition of this carrier is similar to the cell membrane. When the carrier meets with the cell membrane, it fuses with it and delivers the contents into the cytosol. Preliminary results indicate that this new energy delivery technique can provide significant protection to ischemic cells and tissues. The technique has shown very promising effects on normal and ischemic wounds. Three US patents and more than 12 international patents have been filed and the innovation has also been reported to the NIH. Our preliminary results also indicated that high-energy phos- phate contents were severely depleted in human chronic wounds, and treatment with ATP-vesicles in animal wounds increased tissue high-energy contents. Five hypotheses will be tested: (1) high-energy phosphate contents are decreased in chronic diabetic wounds;2) an ischemic wound model created using a minimally invasive surgical technique can be tolerable to diabetic animals;3) intracellular ATP delivery will increase wound tissue energy levels to facilitate healing;(4) by providing energy to wound tissue, improved healing is achieved through coordinated upregulation of growth factors and other healing mechanisms;and (5) direct intracellular energy delivery will enhance wound healing by improved tissue perfusion. These issues have not been explored in the past, but our preliminary results have established the basis for the success of this project. The expansion of usage of the direct intracellular energy delivery is likely to have a major impact on medicine. It will not only improve chronic wound care, but also help our treatment to various ischemic conditions, such as severe trauma, shock, stroke, heart attack, spinal cord injury, cardiopulmonary bypass, organ transplant, and many other acute and chronic ischemic diseases.